The role of AP-1 family transcription factor networks in regulating Th17 cell effector identity PROJECT SUMMARY CD4 T cells can adopt one of two opposing fates: that of a helper T cell (Th) specialized in supporting the clearance of infections, or that of a regulatory T cell (Treg) that functions to attenuate immune responses. Among the diversity of Th subset differentiation options, IL-17A-producing inflammatory Th17 cells stand out as unique by virtue of their relatively high level of inherent plasticity. Indeed, this subset hat normally functions in mucosal immunity against bacteria and fungi can easily adopt features of other T helper subsets when environmental conditions change. While this feature can be advantageous during the clearance of an infection, it is less beneficial during inflammatory disease. Indeed, dysregulated Th17 cell function has been implicated in numerous autoimmune conditions, including Inflammatory Bowel Disease, Multiple Sclerosis, Rheumatoid Arthritis and Psoriasis. Moreover, Th17 cell plasticity exhibited in the context of inflammatory disease tends to take on Th1-like traits, such as expression of IFN? or T-bet, that are also associated with increased pathology. The underlying mechanisms that permit this plasticity are largely unknown. In this regard, we have recently identified several AP-1 family transcription factors with opposing roles in promotion versus limitation of Th17 cell plasticity. CD4 T cells lacking JunB exhibit dysregulated cytokine and transcription factor expression signatures both during in vitro differentiation, and in mouse models of inflammatory disease. In particular, JunB appears to restrain inappropriate Treg and Th1 differentiation. Here, we aim to test the hypothesis that JunB represents a novel controller of Th17 cell effector and regulatory switches, serving as a gate-keeper of Th17 cell plasticity. To this end, in Aim 1 we will perform conditional deletion of JunB using CD4- and Il17a- Cre deleter strains in the context of a fate-mapping reporter mouse to dissect the requirement for JunB in maintaining Th17 cell stability in diverse inflammatory disease and infection conditions. In Aim 2, we plan to decipher the molecular mechanisms of JunB-regulated Th17 stability. In this regard, we will (i) validate the JunB targets that facilitat subset interconversion events; (ii) define novel genomic lineage restriction elements and their mode of regulation by AP-1 complexes; and (iii) define activating and repressing roles of JunB that support Th17 lineage stability. Such mechanistic insight is key to guiding future work aimed at exploiting the AP-1 balance in Th17 cells to divert damaging inflammatory responses into favorable regulatory responses.